Mammalian evolution of human cis-regulatory elements and transcription factor binding sites. Andrews, G., Fan, K., Pratt, H. E., Phalke, N., Zoonomia Consortium§, Karlsson, E. K., Lindblad-Toh, K., Gazal, S., Moore, J. E., Weng, Z., Andrews, G., Armstrong, J. C., Bianchi, M., Birren, B. W., Bredemeyer, K. R., Breit, A. M., Christmas, M. J., Clawson, H., Damas, J., Di Palma, F., Diekhans, M., Dong, M. X., Eizirik, E., Fan, K., Fanter, C., Foley, N. M., Forsberg-Nilsson, K., Garcia, C. J., Gatesy, J., Gazal, S., Genereux, D. P., Goodman, L., Grimshaw, J., Halsey, M. K., Harris, A. J., Hickey, G., Hiller, M., Hindle, A. G., Hubley, R. M., Hughes, G. M., Johnson, J., Juan, D., Kaplow, I. M., Karlsson, E. K., Keough, K. C., Kirilenko, B., Koepfli, K., Korstian, J. M., Kowalczyk, A., Kozyrev, S. V., Lawler, A. J., Lawless, C., Lehmann, T., Levesque, D. L., Lewin, H. A., Li, X., Lind, A., Lindblad-Toh, K., Mackay-Smith, A., Marinescu, V. D., Marques-Bonet, T., Mason, V. C., Meadows, J. R. S., Meyer, W. K., Moore, J. E., Moreira, L. R., Moreno-Santillan, D. D., Morrill, K. M., Muntané, G., Murphy, W. J., Navarro, A., Nweeia, M., Ortmann, S., Osmanski, A., Paten, B., Paulat, N. S., Pfenning, A. R., Phan, B. N., Pollard, K. S., Pratt, H. E., Ray, D. A., Reilly, S. K., Rosen, J. R., Ruf, I., Ryan, L., Ryder, O. A., Sabeti, P. C., Schäffer, D. E., Serres, A., Shapiro, B., Smit, A. F. A., Springer, M., Srinivasan, C., Steiner, C., Storer, J. M., Sullivan, K. A. M., Sullivan, P. F., Sundström, E., Supple, M. A., Swofford, R., Talbot, J., Teeling, E., Turner-Maier, J., Valenzuela, A., Wagner, F., Wallerman, O., Wang, C., Wang, J., Weng, Z., Wilder, A. P., Wirthlin, M. E., Xue, J. R., & Zhang, X. Science, 380(6643):eabn7930, April, 2023.
Mammalian evolution of human cis-regulatory elements and transcription factor binding sites [link]Paper  doi  abstract   bibtex   
Understanding the regulatory landscape of the human genome is a long-standing objective of modern biology. Using the reference-free alignment across 241 mammalian genomes produced by the Zoonomia Consortium, we charted evolutionary trajectories for 0.92 million human candidate cis-regulatory elements (cCREs) and 15.6 million human transcription factor binding sites (TFBSs). We identified 439,461 cCREs and 2,024,062 TFBSs under evolutionary constraint. Genes near constrained elements perform fundamental cellular processes, whereas genes near primate-specific elements are involved in environmental interaction, including odor perception and immune response. About 20% of TFBSs are transposable element–derived and exhibit intricate patterns of gains and losses during primate evolution whereas sequence variants associated with complex traits are enriched in constrained TFBSs. Our annotations illuminate the regulatory functions of the human genome. , INTRODUCTION Mammals, including humans, achieve high levels of organismal complexity largely due to how their proteins are regulated; characterizing the regulatory landscape of the human genome is a longstanding goal of modern biology. Contemporary approaches measure genome-wide biochemical signals, including chromatin accessibility, histone modifications, DNA methylation, and binding of ~1600 transcription factors (TFs) by the human genome. Using these methods, the ENCODE consortium defined almost one million candidate cis-regulatory elements (cCREs). Another approach uses evolutionary conservation to identify potential regulatory regions. We combine these approaches, examining how different functional classes of regulatory elements respond to evolutionary pressures. RATIONALE cCREs tend to be conserved and cCRE classes exhibit varying levels of conservation, suggesting interesting evolutionary dynamics. We examine these dynamics in placental mammals using tools developed by the Zoonomia project: the evolutionary constraint in placental mammals and the reference-free 241-genome alignment. We identify the human cCREs and transcription factor binding sites (TFBSs) conserved in the mammalian lineage, characterize the evolutionary histories of cCREs and TFBSs and identify the driving forces behind their gains and losses and—using biochemical and epigenomic data—assess the likelihood that conserved cCREs and TFBSs are functional in humans and other mammals. RESULTS We explored the ENCODE cCREs derived from epigenomic data and the binding sites of 367 TFs from chromatin immunoprecipitation data. We found a spectrum of mammalian conservation for regulatory elements: on one end lies the highly conserved cCREs and constrained TFBSs, and on the other are primate-specific cCREs and TFBSs overlapping transposable elements (TEs). Conserved elements predominate near genes that function in fundamental cellular processes (metabolism, development) and tend to be functional in other mammalian genomes whereas unconstrained elements lie near genes involved in interaction with the environment. We identified ~439 thousand deeply conserved cCREs (47.5% of cCREs and 4% of the human genome) and 2 million TFBSs (0.8% of the human genome) under mammalian constraint. Using a panel of 69 genome-wide association studies, we found that conserved cCREs and constrained TFBSs achieved high heritability enrichment, demonstrating their utility for functional interpretation of human genetic variants. Meanwhile, more than 85% of primate-specific TFBSs—representing more than 20% of all TFBSs—are derived from TEs. Phylogenetic analysis revealed a staggering number of TFBS clusters sharing patterns of presence and absence across primate genomes and enrichment in specific TE families, suggesting that multiple waves of TE insertion spread these TFBSs during primate evolution. CONCLUSION We charted the evolutionary landscapes of cCREs and TFBSs among placental mammals, identifying a subset of elements under purifying selection in the mammalian lineage. These elements are highly enriched in the human genetic variants associated with a panel of diverse, complex traits, with heritability enrichment contributed by both nucleotides under mammalian and nucleotides under primate constraint. Mammalian evolution of the human regulatory landscape. ( A ) Distribution of human cCREs by the number of genomes they align. ( B ) Projection of cCREs by alignments to the other 240 mammalian genomes. ( C ) Project of HNF4A sites (constrained, red; unconstrained, blue). ( D ) Heritability enrichment for 69 human traits in partitions of TFBSs ordered by evolutionary constraint. ( E ) Heritability enrichment for human traits by subsets of TFBSs.
@article{andrews_mammalian_2023,
	title = {Mammalian evolution of human cis-regulatory elements and transcription factor binding sites},
	volume = {380},
	issn = {0036-8075, 1095-9203},
	url = {https://www.science.org/doi/10.1126/science.abn7930},
	doi = {10.1126/science.abn7930},
	abstract = {Understanding the regulatory landscape of the human genome is a long-standing objective of modern biology. Using the reference-free alignment across 241 mammalian genomes produced by the Zoonomia Consortium, we charted evolutionary trajectories for 0.92 million human candidate cis-regulatory elements (cCREs) and 15.6 million human transcription factor binding sites (TFBSs). We identified 439,461 cCREs and 2,024,062 TFBSs under evolutionary constraint. Genes near constrained elements perform fundamental cellular processes, whereas genes near primate-specific elements are involved in environmental interaction, including odor perception and immune response. About 20\% of TFBSs are transposable element–derived and exhibit intricate patterns of gains and losses during primate evolution whereas sequence variants associated with complex traits are enriched in constrained TFBSs. Our annotations illuminate the regulatory functions of the human genome.
          , 
            
              INTRODUCTION
              Mammals, including humans, achieve high levels of organismal complexity largely due to how their proteins are regulated; characterizing the regulatory landscape of the human genome is a longstanding goal of modern biology. Contemporary approaches measure genome-wide biochemical signals, including chromatin accessibility, histone modifications, DNA methylation, and binding of {\textasciitilde}1600 transcription factors (TFs) by the human genome. Using these methods, the ENCODE consortium defined almost one million candidate cis-regulatory elements (cCREs). Another approach uses evolutionary conservation to identify potential regulatory regions. We combine these approaches, examining how different functional classes of regulatory elements respond to evolutionary pressures.
            
            
              RATIONALE
              cCREs tend to be conserved and cCRE classes exhibit varying levels of conservation, suggesting interesting evolutionary dynamics. We examine these dynamics in placental mammals using tools developed by the Zoonomia project: the evolutionary constraint in placental mammals and the reference-free 241-genome alignment. We identify the human cCREs and transcription factor binding sites (TFBSs) conserved in the mammalian lineage, characterize the evolutionary histories of cCREs and TFBSs and identify the driving forces behind their gains and losses and—using biochemical and epigenomic data—assess the likelihood that conserved cCREs and TFBSs are functional in humans and other mammals.
            
            
              RESULTS
              We explored the ENCODE cCREs derived from epigenomic data and the binding sites of 367 TFs from chromatin immunoprecipitation data. We found a spectrum of mammalian conservation for regulatory elements: on one end lies the highly conserved cCREs and constrained TFBSs, and on the other are primate-specific cCREs and TFBSs overlapping transposable elements (TEs). Conserved elements predominate near genes that function in fundamental cellular processes (metabolism, development) and tend to be functional in other mammalian genomes whereas unconstrained elements lie near genes involved in interaction with the environment. We identified {\textasciitilde}439 thousand deeply conserved cCREs (47.5\% of cCREs and 4\% of the human genome) and 2 million TFBSs (0.8\% of the human genome) under mammalian constraint. Using a panel of 69 genome-wide association studies, we found that conserved cCREs and constrained TFBSs achieved high heritability enrichment, demonstrating their utility for functional interpretation of human genetic variants. Meanwhile, more than 85\% of primate-specific TFBSs—representing more than 20\% of all TFBSs—are derived from TEs. Phylogenetic analysis revealed a staggering number of TFBS clusters sharing patterns of presence and absence across primate genomes and enrichment in specific TE families, suggesting that multiple waves of TE insertion spread these TFBSs during primate evolution.
            
            
              CONCLUSION
              We charted the evolutionary landscapes of cCREs and TFBSs among placental mammals, identifying a subset of elements under purifying selection in the mammalian lineage. These elements are highly enriched in the human genetic variants associated with a panel of diverse, complex traits, with heritability enrichment contributed by both nucleotides under mammalian and nucleotides under primate constraint.
              
                
                  Mammalian evolution of the human regulatory landscape.
                  
                    (
                    A
                    ) Distribution of human cCREs by the number of genomes they align. (
                    B
                    ) Projection of cCREs by alignments to the other 240 mammalian genomes. (
                    C
                    ) Project of HNF4A sites (constrained, red; unconstrained, blue). (
                    D
                    ) Heritability enrichment for 69 human traits in partitions of TFBSs ordered by evolutionary constraint. (
                    E
                    ) Heritability enrichment for human traits by subsets of TFBSs.},
	language = {en},
	number = {6643},
	urldate = {2023-04-28},
	journal = {Science},
	author = {Andrews, Gregory and Fan, Kaili and Pratt, Henry E. and Phalke, Nishigandha and {Zoonomia Consortium§} and Karlsson, Elinor K. and Lindblad-Toh, Kerstin and Gazal, Steven and Moore, Jill E. and Weng, Zhiping and Andrews, Gregory and Armstrong, Joel C. and Bianchi, Matteo and Birren, Bruce W. and Bredemeyer, Kevin R. and Breit, Ana M. and Christmas, Matthew J. and Clawson, Hiram and Damas, Joana and Di Palma, Federica and Diekhans, Mark and Dong, Michael X. and Eizirik, Eduardo and Fan, Kaili and Fanter, Cornelia and Foley, Nicole M. and Forsberg-Nilsson, Karin and Garcia, Carlos J. and Gatesy, John and Gazal, Steven and Genereux, Diane P. and Goodman, Linda and Grimshaw, Jenna and Halsey, Michaela K. and Harris, Andrew J. and Hickey, Glenn and Hiller, Michael and Hindle, Allyson G. and Hubley, Robert M. and Hughes, Graham M. and Johnson, Jeremy and Juan, David and Kaplow, Irene M. and Karlsson, Elinor K. and Keough, Kathleen C. and Kirilenko, Bogdan and Koepfli, Klaus-Peter and Korstian, Jennifer M. and Kowalczyk, Amanda and Kozyrev, Sergey V. and Lawler, Alyssa J. and Lawless, Colleen and Lehmann, Thomas and Levesque, Danielle L. and Lewin, Harris A. and Li, Xue and Lind, Abigail and Lindblad-Toh, Kerstin and Mackay-Smith, Ava and Marinescu, Voichita D. and Marques-Bonet, Tomas and Mason, Victor C. and Meadows, Jennifer R. S. and Meyer, Wynn K. and Moore, Jill E. and Moreira, Lucas R. and Moreno-Santillan, Diana D. and Morrill, Kathleen M. and Muntané, Gerard and Murphy, William J. and Navarro, Arcadi and Nweeia, Martin and Ortmann, Sylvia and Osmanski, Austin and Paten, Benedict and Paulat, Nicole S. and Pfenning, Andreas R. and Phan, BaDoi N. and Pollard, Katherine S. and Pratt, Henry E. and Ray, David A. and Reilly, Steven K. and Rosen, Jeb R. and Ruf, Irina and Ryan, Louise and Ryder, Oliver A. and Sabeti, Pardis C. and Schäffer, Daniel E. and Serres, Aitor and Shapiro, Beth and Smit, Arian F. A. and Springer, Mark and Srinivasan, Chaitanya and Steiner, Cynthia and Storer, Jessica M. and Sullivan, Kevin A. M. and Sullivan, Patrick F. and Sundström, Elisabeth and Supple, Megan A. and Swofford, Ross and Talbot, Joy-El and Teeling, Emma and Turner-Maier, Jason and Valenzuela, Alejandro and Wagner, Franziska and Wallerman, Ola and Wang, Chao and Wang, Juehan and Weng, Zhiping and Wilder, Aryn P. and Wirthlin, Morgan E. and Xue, James R. and Zhang, Xiaomeng},
	month = apr,
	year = {2023},
	keywords = {Zoonomia},
	pages = {eabn7930},
}
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